GUIDELINE for Gammaherpesvirus infection in cats

These guidelines were drafted by Herman Egberink.

Key points

• Felid gammaherpesvirus 1 (Felis catus gammaherpesvirus 1; FcaGHV1) infections are endemic in the cat population.
• Risk factors associated with FcaGHV1 infection are: male sex, older age, non-pedigree status and coinfections with FIV and haemoplasmas.
• Based on identified risk factors and associated co-infections, aggressive behaviour is a plausible mode of transmission between cats.
• Studies so far do not support a role for FcaGHV1 in the development of lymphomas or other carcinomas.

Agent properties

Herpesvirus virions contain a phospholipid envelope and have genomes of linear, double-stranded DNA. The family Orthoherpesviridae (order Herpesvirales) is subdivided into three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae (GHV). The GHVs are further classified into seven genera: Bossavirus, Lymphocryptovirus Macavirus, Manticavirus, Patagivirus, Percavirus and Rhadinovirus. GHVs are known to infect humans and different animal species, causing persistent and presumably lifelong infections with restricted but recurrent viral replication (Ehlers et al., 2008; Fenner, 2017). This property is known as latency. Members in the subfamily GHV are lymphotropic and establish latency in lymphocytes. Felid Gammaherpesvirus 1 (Felis catus gammaherpesvirus 1; FcaGHV1) was first described in 2014 and classified as a gammaherpesvirus within the genus Percavirus (Beatty et al., 2014). FcaGHV1 is not related to feline herpesvirus, which is a  member of the subfamily Alphaherpesvirinae and the cause of upper respiratory and ocular disease (Thiry et al., 2009).

Epidemiology

Since the first description of FcaGHV1 infections in cats in 2014, several studies on the prevalence of this virus infection in populations of cats from different countries have been published. In these studies, the infection with FcaGHV1 was determined by detection of viral DNA by quantitative polymerase chain reaction (qPCR), mainly in blood but also in tissues, and by the demonstration of specific antibodies in blood (seroprevalence). Antibody testing also allows the identification of cats that have been exposed to FcaGHV1 infection but due to the latent state of infection they do not express DNA or DNA is only present in very low amounts (Stutzman-Rodriguez et al., 2016). Results of these studies show a worldwide distribution of FcaGHV1 infection. Using PCR, infections have been reported in Europe, Australia, USA,  Japan, Brazil and Singapore with 1-23.6% of cats demonstrating viral DNA within their blood (Beatty et al., 2014; Troyer et al., 2014; Ertl et al., 2015; McLuckie et al., 2016a; Kurissio et al., 2018; Makundi et al., 2018; Caringella et al., 2019; Novacco et al., 2019). For the detection of antibodies, an ELISA was developed with two recombinant proteins (expressed from ORF38 and ORF52) that showed the most consistent and strong antibody response. As expected, the seroprevalence was found to be higher than the molecular prevalence of FcaGHV1 DNA, with 32% of samples being seropositive compared to 15% being qPCR positive (Stutzman-Rodriguez et al., 2016). All but one qPCR positive animals were seropositive (Stutzman-Rodriguez et al., 2016).

Possible risk factors for FcaGHV1 infection have been identified in several studies on the prevalence of FcaGHV1 infections. Factors significantly associated with FcaGHV1 detection include male sex, older age, non-pedigree status and coinfections with FIV and haemoplasmas (McLuckie et al., 2016a; Novacco et al., 2019). Also, FcaGHV1 viral load was significantly higher in FIV-infected cats compared with matched controls. Co-infection with FeLV was reported to be associated with FcaGHV1 infection in one study in cats from Singapore (Beatty et al., 2014). In a study from Switzerland FeLV viraemia tended to be associated with FcaGHV1 (but not significantly), with high FcaGHV1 blood loads found more frequently in FeLV viraemic cats as compared to uninfected controls (Novacco et al., 2019). However, in other epidemiological studies an association with FeLV infection could not be confirmed (McLuckie et al., 2017; Kurissio et al., 2018).

FcaGHV1 DNA was detected in oropharyngeal swabs from 26 out of 155 animals (16.8%), which supports the role of the oropharynx as a site of virus shedding (Rose et al., 2022). Using in situ hybridization, viral DNA was detected in salivary epithelium but not in other oronasal tissues. Salivary epithelium was suggested also as a potential site of FcaGHV1 persistence (Rose et al., 2022). The presence of FcaGHV1 in saliva and the identified risk factors (male sex, older age, non-pedigree status, coinfections with FIV and haemoplasmas) support horizontal transmission, plausibly during aggressive behaviour (Beatty et al., 2019). Both FIV and haemoplasmas are associated with FcaGHV1 detection. For FIV, the major route of natural transmission is believed to be via the inoculation of saliva during fighting (Yamamoto et al., 1989). For  infection with haemoplasmas intercat aggression is also considered a mode of transmission (Tasker et al., 2018).

Since the first demonstration of a feline GHV in 2014, novel GHVs have been identified in other felids: in bobcats (Lynx rufus, LruGHV1 and LruGHV2), in pumas (Puma concolor, PcoGHV1), in ocelots (Leopardus pardalis, LpaGHV1) (Troyer et al., 2014; Lozano et al., 2015) and in the Canada Lynx (Lynx canadensis, LcaGHV1). In an earlier study a GHV was identified in an African lion (PleoGHV1)(Ehlers et al., 2008). All of the previously identified feline GHVs have been found to cluster within the genus Percavirus, with the exceptions of PcoGHV1 and PleoGHV1, which belong to the genus Rhadinovirus (Troyer et al., 2014; Lozano et al., 2015).

GHVs are considered to be host specific. But FcaGHV1 may infect feline species other than the domestic cat as supported by the identification of FcaGHV1 from a Tsushima leopard cat on Tsushima Island, Japan (Makundi et al., 2018).

Pathogenesis and clinical signs

Most of the GHVs are non-pathogenic in their natural host under normal conditions but are associated with disease under conditions of immunosuppression or infection of a non-adapted species (Fenner, 2017). Gammaherpesviruses are lymphotropic: FcaGHV1 was also detected in B- and T-lymphocytes in the blood of persistently infected, asymptomatic cats (McLuckie et al., 2016b).

The identification of an association of gammaherpesvirus infection with disease is expected to be difficult since disease may be an occasional outcome years after infection and may not only depend on immune dysfunction but also on several other host factors, such as coinfections or genetic background (Beatty et al., 2019). Several studies have tried to determine a potential role for FcaGHV1 in disease development (Beatty et al., 2014). In one study FcaGHV1 DNA positive cats were found more likely to be classified as sick, where being healthy or sick was based on a qualitative measure of the health status by a veterinarian (Beatty et al., 2014). But, so far, no clear evidence has been found for an association of FcaGHV1 with a specific disorder.

Some GHVs may induce oncogenic transformation of lymphocytes or epithelial cells, with Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) as well-known examples of this pathogenesis in humans with HIV (Weed and Damania, 2019). EBV can cause Burkitt’s lymphoma and nasopharyngeal carcinoma in humans (Cesarman, 2011).

The knowledge of a role for human GHV in the development of lymphomas in immunodeficient patients with HIV was the trigger to investigate the existence of feline GHV in the development of lymphomas in FIV infected cats. FIV infected cats are about five times more likely to develop lymphoid malignancies compared to uninfected cats (Hartmann, 2011). In FIV infected cats a higher prevalence of FcaGHV1 infection has been found and also higher FcaGHV1 loads are present in FIV infected cats than in control cats matched for sex and age (Beatty et al., 2014; Ertl et al., 2015). Nonetheless, no potential link between FIV and FcaGHV1 infection and the development of lymphomas has been shown in the few studies that have been published so far. In one study using in situ hybridization to detect viral DNA, only in 1 out of 23 cases of FIV-associated lymphomas was FcaGHV1 DNA identified (Aghazadeh et al., 2018). Similarly, none of the tissue samples from 17 cats with lymphoma tested PCR positive for FcaGHV1 DNA in a Swiss study (Novacco et al., 2019). In another study FcaGHV1 was not identified in four cats with rapidly progressive FIV-associated lymphoma (Magden et al., 2013). Finally, no association was found between FcaGHV1 infection and the development of high-grade lymphoma (McLuckie et al., 2016a).

Diagnosis, prevention and control

A GHV-specific PCR targeting the gB glycoprotein gene can be used to detect GHV DNA in blood or tissue specimens (Troyer et al., 2014). This assay, together with serological assays, are mainly used for research purposes. Since a role of FcaGHV1 in causing disease has so far not been proven, the demonstration of FcaGHV1 has no prognostic or clinical significance for clinical practice.

Zoonotic risk

There is no indication that FcaGHV causes a zoonotic infection.

 Acknowledgement

ABCD Europe gratefully acknowledges the support of Boehringer Ingelheim (the founding sponsor of the ABCD), Virbac, IDEXX GmbH and MSD Animal Health.

References

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